Human IGF-I (hIGF-I) is a peptide present in plasma and other body fluids. It has been purified from human plasma and the complete amino acid sequence is known. The primary sequence comprises 70 amino acids, including 3 disulphide bonds. Moreover, purified IGF-I:s from plasma of other species show extensive sequence homologies to hIGF-I.
hIGF-I can stimulate growth of a wide range of cell types. It has both systemic and local effects and is present in the circulation mainly associated with different binding proteins, six of which are sequenced (IGFBP1-6). The binding proteins appear to modulate the biological functions and availability of IGF-I variably. IGF-I analogues with changed biological activities seemingly related to changes of affinities to the binding proteins have been produced. IGF-I appears to act mainly through the IGF-type 1 receptor exposed on the outer surface of many different cell types. However, the relative specificity of action may vary at the cell level, for example, due to varying influence of binding proteins. The structures of the IGF-I and insulin receptors are closely homologous, but binding of IGF-I and insulin show only limited cross-reactivity.
Because of the scarcity of purified plasma hIGF-I, there was a great need to develop methodology for a commercial scale production. Nowadays such large scale production of hIGF-I can readily be achieved by using recombinant DNA techniques.
IGF-I is primarily involved in mediating the somatogenic effects of growth hormone (GH). As a result of studies with preparations of recombinant DNA derived hIGF-I, it has been demonstrated that it promotes skeletal growth and skeletal muscle protein synthesis. Moreover, hIGF-I is also effective for the treatment or prevention of catabolic states (WO 92/03154)).
In WO 91/12018 (Ballard et al.) the therapeutic use of IGF-I, or a peptide analogue thereof, for gastrointestinal disease or the treatment of the shortened gut after surgery was disclosed.
It has also been found that IGF-I improves the regeneration of transected periferal nerves (EP 308 386) and it has previously been demonstrated in vitro that IGF-I promotes actin synthesis in myocytes in culture (Florini, J. R., Muscle and Nerve, 10 (1987) 577-598), and contractility of neonatal rat cardiocytes (Vetter, U. et al., Basic Res. Cardiol. 83 (1988) 647-654.
Large doses of hIGF-I do lower blood glucose in non-diabetic animals and humans (Zapf J. et al. J Clin-Invest, Jun Vol:77(6) (1986) 1768-75 and Guler H-P et al, N Engl. J. Med, 317 (1987) 137-140). In these studies the hypoglycaemic effect of hIGF-I was around 1.5-7% of that of insulin. Recent studies in the depancreatised dog demonstrated that as an agent for lowering blood glucose hIGF-I was 8-11% as potent as insulin (Giacca A. et al., Diabetes, 39 (1990) 340-347). However, these studies also demonstrated that the metabolic effects of IGF-I may be quite distinct from those of insulin. The glucose lowering effects of IGF-I were largely mediated by increased glucose uptake, while glucose production rates remained unchanged. One explanation for this observation might be the relative paucity of IGF-I receptors in adult liver (Caro J. F. et al., J. Clin. Invest, 81 (1988) 976-981). It is likely that the effects of IGF-I are largely mediated through muscle. Similar distinctions in the distribution of receptors may explain the less potent antilipolytic effects of IGF-I as compared to insulin in vitro (Bolinder et al, J. Clin. Endocrinol. Metab, 65, (1987) 732-737) and in vivo (Zapf J. et al. 1986, Guler H-P et al. 1987, Giacca A et al. 1990). IGF-I decreases proteolysis and reduces amino acid levels in non-diabetic rats (Jacob R. et al., J Clin. Invest, 83, (1989) 1717-1723). Furthermore, in the studies of Giacca A. et al. ,1990, a rise in lactate was observed which did not occur with an equipotent dose (for glucose lowering) of insulin.
IGF-I circulates predominantly as a large 150K complex (IGFBP3) comprising a 53K GH-dependent acid stable IGF binding component and an acid labile subunit. The smaller 28-35K binding protein (IGFBP1) is not growth hormone dependent and shows a marked circadian variation which is inversely related to insulin (Brismar K. et al., J Endocrinol Invest, 11(1988) 599-602, Cotterill A. M. et al, J Clin Endocrinol Metabol, 67 (1988) 882-887, Holly J. M. P. et al., Clin Endocrinol, 29 (1988) 667-675). Measured circulating IGF-I level appears to be mainly determined by the available capacity of IGFBP3 whereas IGFBP1 seems to be primarily involved in other functions such as transport of IGF-I from the circulating pool or modulation of biological actions in the tissues (Holly J. M. P. et al., J Endocrinol, 121 (1989) 383-387, and Diabetic Medicine, 7 (1990) 618-23).
Insulin deficiency also results in high levels of IGFBP1 which is believed to inhibit the biological activity of IGF-I (Taylor A. M. et al., Clin Endocrinol, 32 (1990) 229-239).
Age-related changes in plasma IGF-I in healthy subjects have been investigated (Smith C. P. et al, J Clin. Endocrin. Metab, Vol 68, No 5, (1989) 932-937). It was found that basal plasma IGF-I concentrations rose significantly throughout puberty and declined to prepubertal levels by the third decade of life. The concentration was about 1 U/ml before and after puberty and about 2 U/ml during puberty.
It was not previously known how the different IGFBP profile in diabetics would affect the bioavailibility or bioactivity of endogenous or exogenously administered IGF-I.
Increased overnight GH serum concentrations have been compared between diabetic and normal adolescents (Edge J. A. et al, J. Clin. Endocrinol. metab, Vol. 71, No 5, (1990) 1356-1362) and it was found that GH baseline and peak levels were higher in the diabetic than in the control subjects.
In EP 331 630 (Ciba-Geigy) a method is disclosed for treatment and preventing secondary effects of hyperinsulinaemia in Type 1 diabetes mellitus by administrating hIGF-I. In the description the dose of hIGF-I used is around 500 .mu.g/kg/day. hIGF-I was given to two healthy (non-diabetic) subjects receiving 20 .mu.g/kg/h during six days by continuous subcutaneous infusion. The amount given per day is 10 times the endogenous production of hIGF-I (approximately 50 .mu.g/kg/day). With such a high dose of hIGF-I an insulin-like effect is to be expected.
The authors interpreted the results obtained as indicating that these high doses of IGF-I resulted in a decrease of insulin degradation and a prolongation of its half-life. They concluded that hIGF-I makes the organism more sensitive to insulin and therefore a lower dose of insulin can be used. Thus, by administration of hIGF-I, less exogenous insulin would be needed and hyperinsulinaemia due to large doses of insulin can be avoided or minimised. However, the route of administration and particularly the high doses used in the example have a very limited clinical applicability. The dose 480 .mu.g/kg/day given as a continuous infusion results in very high (supraphysiological) serum levels of IGF-I. Such concentrations cannot be regarded as safe and clinically applicable.
In contrast to the findings in EP 331 630, we have found that a physiological restoration of circulating IGF-1 levels gives reduced GH levels through a feed back mechanism. This normalisation of GH and IGF-I levels lead to an increased sensivity for insulin and to a reduction in the dawn phenomenon (the rapid increase in the morning blood glucose levels seen in type 1 diabetics) and thereby providing better long term control.
The possible clinical value of a therapy with IGF-I to restore physiological IGF-I levels and thereby alter the growth hormone/IGF-I axis, have not earlier been considered.